My congratulations are extended to Meenu Singh and Rashmi R Das for a very comprehensive review of the zinc for common cold literature. However, some comments are needed concerning the Eby et al. 1984 report, flavor issues and where we need to go next.
Concerning the original 1984 Eby, Davis and Halcomb article
Our original 1984 article started this line of inquiry by showing that it was possible to shorten common colds by 7 days (P = 0.0005) with 23 mg zinc (zinc gluconate) lozenges when taken each two wakeful hours. These lozenges (unflavored and unsweetened dietary supplement tablets) lasted about 30 minutes in the mouth which provided sufficient time for local absorption into oral tissues. This protocol was developed after observing that 50 mg zinc (zinc gluconate) tablets slowly dissolved in the mouth of a 3-year old child with acute lymphocytic leukemia (T-cell) resulted in her severe common colds disappearing within 2 hours without further treatment and many similar informal observations in the general community.
Our report has drawn some criticism, mainly since the taste of the zinc gluconate lozenges was modestly objectionable resulting in more dropouts in the zinc-treated group than in the placebo-treated group. Bias would occur if zinc-treated subjects who received little or no benefit selectively dropped out or failed to return reports. We were concerned about this potential for bias, and to protect our results we estimated the maximum effect of such bias by assuming that all dropouts and all non-reporters in both zinc and placebo treatment groups received no benefit and responded as if they were on placebo. The effect of zinc in that analysis remained substantial and statistically strong (P = 0.007), and this potential bias was shown to be irrelevant. These modifications to our main results were published in our Discussion section on page 23 right-hand column, but they have been ignored in reviews by others, thus adversely biasing results of several critical reviews. Therefore, I am disappointed that this error was also committed by Singh and Das.
Flavor and flavor-masking issues
Concern about blinding evolved from concern over “bad taste” of zinc lozenges. There is much difference in the taste of zinc lozenges, which should be considered in evaluating bias. Zinc gluconate in tablets with no other soluble ingredients1 are moderately objectionable tasting, but tolerable, to most people. Zinc gluconate releases 72% of its zinc as ionic zinc at physiologic pH 7.4. Zinc gluconate can be sweetened without bitterness using a fructose tablet base as was done in the Al-Nakib trial at the Great Britain Common Cold Unit. However, mixing zinc gluconate with any other sweetener, especially sucrose and/or dextrose, results in products that age within 30 days to be as bitter as the bitterest substance known, sucrose octaacetate. This unexpected and adverse effect caused researchers to search for alternatives to zinc gluconate and for ways to flavor-mask zinc gluconate. Extreme bitterness likely affected only the results of Weisman et al., although they compensated by using very small amounts of zinc.
Although pure zinc acetate, which releases 100% ionic zinc at physiologic pH 7.4,2 tastes vastly more vile than pure zinc gluconate, it is easily flavor-masked by a variety of sweeteners in either hard-candy compositions such as the lozenges tested by Prasad et al. or compressed tablets as tested by Prasad et al. and Petrus et al. These zinc acetate lozenges did not contain flavor-masking additives. Zinc acetate tastes and works best when present in a 1:100 ratio with dextrose in very highly compressed tablets which last about 30 minutes when being dissolved in the mouth. One failure occurred in effervescent lozenges containing zinc acetate which were flavor-masked with tartaric acid and sodium bicarbonate, resulting in elimination of ionic zinc.,
Citric acid was used to flavor-mask the objectionable taste of zinc gluconate in a corn syrup and sucrose hard candy lozenge. Citric acid has a high affinity for ionic zinc and no zinc ions were available for absorption into oral tissues, resulting in clinical failure.2 Due to its pleasant taste, this formula is commonly used in commercial zinc lozenges in the United States resulting in no effect against common colds other than nutritional support.
Glycine was used to flavor-mask zinc gluconate in several clinical trials, with two, showing efficacy and one showing lack of efficacy. Variability in results may have been caused by glycine since it eliminates about one half (or more) of the ionic zinc from lozenges.2 NOTE: This formula does not release “over 90% ionic zinc” at physiologic pH 7.4 as portrayed by Sing and Das, but it does release that amount at pH 5.0, a nonsense pH.
Availability of ionic zinc is dependent upon a number of variables including pH, concentration, temperature and compound being tested, and such is a subject of extensive research by solution equilibrium inorganic chemists .2
Consequently, to say that effective zinc lozenges have an objectionable taste that can bias clinical trials is not necessarily factual. The worst possible taste and most bias in effective zinc lozenges results from zinc gluconate in a non-fructose carbohydrate hard candy or tablet base, which was found only in the Weisman trial.4 Zinc gluconate in a non-soluble tablet base is about 1/10th as objectionable,1 while zinc gluconate in a fructose tablet base,3 zinc gluconate-glycine11, 12, 13 and zinc acetate5,6,7 in a 1:100 dextrose tablet base are each commercially acceptable in taste. However, zinc acetate lozenges are potentially the most effective, use the least zinc, and are the best tasting. Zinc acetate lozenges also had the least potential for bias due to their pleasant taste, although they had an astringent mouth-feel demonstrating release of zinc ions. A perfect placebo would have been astringent in mouth-feel, perhaps like tannin. Pursuit of a pleasant tasting and effective zinc lozenge has led to both clinical successes and failures, and the large variety of formulations has greatly complicated the analytical picture.
What is next?
As the researcher that originally discovered the effect of ionic zinc from throat lozenges on the duration of common colds, I am very concerned that the statement “zinc is good for colds” released on nearly every U.S. national TV news program, radio station and newspaper (and perhaps also in Europe, Australia and elsewhere) due to loose journalistic interpretation of the Singh and Das report. It is far too broad and too simplistic to be accurate, and it will likely lead to OTC products that will not have the features necessary to shorten colds more than a day, thus 26 years of zinc lozenge research could be lost and perhaps not regained for decades or a century. These features were previously described in my 2009 review.2 That review showed dose-response linearity of lozenges by their ionic zinc content on the duration of colds. It showed that reductions in the mean (P=0.001) and median (P=0.004) durations of common colds were statistically significant and meaningful.
It also showed that the effects of a compressed dextrose tablet containing 18 mg of zinc (zinc acetate dyhydrate - 60 mg), glycerol monostearate as a tablet lubricant and peppermint oil on silica gel, which happens to be a 2X homeopathic Zincum aceticum formula, is expected to shorten common colds by 7 days. These lozenges released the same amount of ionic zinc as did our 23 mg zinc gluconate lozenges tested in 1984.1 They are 1.9 cm (¾ inch) diameter and 1.27 cm (1/2 inch) thick tablets which are best produced on heavy production machines like a Stokes 328-2 tablet press. Magnesium stearate was not used as a lubricant due to concerns about concentrated magnesium greatly stimulating rhinovirus replication.
These zinc acetate lozenges are pleasant tasting and taste like peppermint candy. If these tablets are compressed to a sufficient hardness, they will dissolve in the mouth in about 30 minutes. Fick's laws of membrane permeability show that the amount of a solute absorbed across a membrane is time and concentration dependent. Thirty minutes is a reasonable time for oral dissolution. Also, the dextrose-based formula does not excessively promote saliva production. I suggest that it is now time to focus on this basic formulation and go forward with research on it. I see no necessity to focus on zinc compounds that do not release 100% of their zinc as ionic zinc, or on products that dissolve too fast for significant oral absorption, or on products that contain too little ionic zinc to be effective. From the time of contact with the oral mucosa aspects of Fick's laws, the use of syrups or orally ingested tablets to treat common colds are not advised if large reductions in their duration are desired.
Perhaps there is also a requirement to consider how ionic zinc works in shortening colds and the work of Merluzzi et al. in showing that ionic zinc, but not bound zinc, inhibits the replication of rhinoviruses should be considered vital, along with the extensive pioneering work of Korant and Butterworth in showing the inhibitor effects of ionic zinc on rhinoviral replication., ,, , , , ,  These articles should give support to the notion that the main effect of ionic zinc in treating common colds is by rhinovirus replication inhibition.
Although I cannot see into the future, I have proposed here what I believe to be the most likely route to successful treatment of common colds, and I hope that new zinc lozenge researchers will follow my advice. If they do follow my advice, they should be able to demonstrate in a coordinated manner the massive benefits of zinc in treating colds in just a few years, rather than in the decades or centuries that I expect from future distortions of the literature if researchers continue to test faulty products and publish those results. Provided with good results, manufactures can follow through with products that will shorten colds by a week in the general public. Then, and only then, can we say that there is a cure for the common cold!
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